Iron deficiency remains the most widespread micronutrient deficiency worldwide, whereas Fe overload has been increasingly appreciated as a contributor to many types of chronic disease, such as type II diabetes, cirrhosis, cancer and cardiomyopathy. We hypothesize that evolutionary adaptations in genes involved in non- heme Fe metabolism, in East Asian populations, have resulted in an increased efficiency of Fe absorption even in the face of adequate Fe stores. Our preliminary data from multiple GWA studies on blood Fe status in populations of European and/or East Asian genetic backgrounds, found novel and statistically significant enrichment for associations with Fe status in other genes that have been shown to regulate Fe via multiple biological pathways, suggesting a highly polygenic genetic architecture underlying Fe absorption and regulation in humans. The enrichment of associations of variations in these genes with blood Fe status at a pathway level implies that genetic variation affecting Fe absorption and regulation has yet to be exhaustively identified. We propose to employ a direct functional measure of an individuals' capacity to absorb and utilize non-heme Fe to build an unbiased genetic architecture of (non-heme) Fe utilization in humans. We are uniquely positioned to address genetic determinants of Fe homeostasis using a multidisciplinary approach. We will first undertake a functional study to investigate population differences in non-heme Fe absorption in a large cohort of East Asians (n=252) and Northern Europeans (n=252). Population differences in Fe absorption will be evaluated in relation to a fixed level of Fe stores (Aim 1). Three hormones, hepcidin, erythroferrone and erythropoietin, are now known to regulate systemic Fe homeostasis. In Aim 2, we will characterize these hormones and additional hematological, and Fe status biomarkers in all 502 participants to develop models to investigate variability in Fe absorption that can be captured by existing Fe biomarkers and regulatory hormones as a function of age, gender and population. To fully capture known and novel genetic variations underlying Fe absorption in different populations, genetic variants will be measured in all 504 participants in Aim 1 using the Illumina Infinium BeadChip. We will investigate the genetic contribution to Fe absorption, Fe status and Fe regulatory hormones and explore possible differences as a function of genetically confirmed ancestry (Aim 3). Our approach thus has the potential to identify novel relevant Fe homeostatic pathways that are associated with Fe status and more importantly that may be driving variability in Fe absorption, the key regulatory site of Fe homeostasis. These studies will provide novel information on human dietary adaptation that will shed light on the genetic basis of population discrepancy in traits and disease susceptibility, and will guide future genome-informed nutritional practices.